Preparation method of Linzaagolix

Abstract

The invention discloses a preparation method of Linzagolix, which comprises the following steps: taking 2, 3-difluoro-6-methoxybenzyl alcohol as a raw material, under the action of alkali and phosphine ligand, carrying out Mitsunobu reaction on 2, 3-difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol to obtain a compound A, sequentially carrying out nitration reaction and reduction reaction on the compound A to obtain a compound C, and carrying out recrystallization on the compound C to obtain the Linzagolix. Under the alkaline condition and the action of triphosgene, the compound C and 4-aminothiophene-2, 3-dimethyl dicarboxylate hydrochloride are subjected to a one-pot condensation reaction to obtain a compound D, and the compound D reacts under the alkaline condition to generate Linzaolix. According to the invention, the synthesis process of Linazagolix is shortened to five steps, the reaction condition is mild, the operation is simpler and more convenient, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis and relates to a method for preparing the GnRHr antagonist Linzagolix. Background Technology

[0002] Gonadotropin-releasing hormone (GnRH) is a glycoprotein hormone synthesized and secreted by the anterior pituitary gland. As a key factor in the pituitary-gonadal axis, it stimulates the pituitary gland to periodically secrete gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) by activating G protein-coupled receptors (GPCRs) and gonadotropin-releasing hormone receptors (GnRHr) on its cell surface. Abnormal expression of the GnRHr signaling pathway is closely related to the occurrence and development of diseases such as uterine fibroids, endometriosis, prostate cancer, and breast cancer. According to WHO data, endometriosis affects approximately 10% (190 million) of women of reproductive age worldwide. Currently, there is no cure, and the recurrence rate after surgery can reach 50% within 5 years; therefore, there is a huge clinical need to develop GnRH drugs.

[0003] Linzagolix is ​​a novel oral small-molecule GnRHr antagonist that competitively binds directly to pituitary GnRHr, rapidly inducing a dose-dependent decrease in luteinizing hormone (LH) and its downstream estrogen (E2) levels, thereby exerting its therapeutic effect. Studies have shown that Linzagolix has a superior clinical response rate and amenorrhea rate compared to Elagolix and Relugolix. Unlike Elagolix and Relugolix, which cannot be used at high doses for more than 6 months, Linzagolix can be used at both high and low doses for long-term use, making it the first small-molecule GnRHr antagonist with flexible dosing.

[0004]

[0005] The original research was conducted by Kissei Pharmaceuticals of Japan, which disclosed a method for preparing linzagorithm in patent WO2014042176A1. Using 2,3-difluoro-6-methoxybenzyl alcohol as a starting material, linzagorithm was obtained through eight steps including chlorination, nucleophilic substitution, nitration, reduction, condensation, and hydrolysis. The synthetic route is as follows:

[0006]

[0007]

[0008] The above-mentioned process involves a relatively long reaction route, and the reduction reaction uses hydrogen gas, which places high demands on equipment and results in high costs for industrial production. Therefore, it is particularly necessary to develop a synthesis process with a shorter route that is easier to industrialize. Summary of the Invention

[0009] The purpose of this invention is to address the shortcomings of the original Linzagolix process by providing a new method for preparing Linzagolix, which shortens the 8-step reaction of the original process to 5 steps, improves reaction efficiency, and is simpler to operate and easier to industrialize.

[0010] The objective of this invention is achieved through the following technical solution:

[0011] A method for preparing Linzagolix, the synthetic route is as follows:

[0012]

[0013] This includes: using 2,3-difluoro-6-methoxybenzyl alcohol as a starting material, under the action of a base and a phosphine ligand, 2,3-difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol undergo a photo-tracing reaction (Mitsunobu reaction) to give 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene (compound A). 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene then undergoes nitration and reduction reactions to give 5-[(2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-methoxyaniline (compound C). Under alkaline conditions and the action of triphosgene, 5-[(2,3-difluoro-6-methoxy)oxy)-2-fluoro-4-methoxyaniline (compound C) undergoes further reactions. A one-pot condensation reaction of methylbenzyl)oxy)-2-fluoro-4-methoxyaniline with dimethyl 4-aminothiophene-2,3-dicarboxylate hydrochloride yields a thiophene urea derivative (compound D, 4-[[[[5-[(2,3-difluoro-6-methoxyphenyl)methoxy]-2-fluoro-4-methoxyphenyl]amino]carbonyl]amino]-2,3-thiophene dicarboxylate). The thiophene urea derivative reacts under alkaline conditions to generate Linzagolix (3-(5-((2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5 carboxylic acid, i.e., linzagoli).

[0014] Specifically, a method for preparing Linzagolix includes the following steps:

[0015] Step (1): 2,3-Difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol are dissolved in a reaction solvent. Under the action of a base and a phosphine ligand, 2,3-difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol undergo a photo-tracing reaction to obtain 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene;

[0016] Step (2): In an acidic solvent, compound A undergoes a nitration reaction with nitric acid to obtain compound B (1,2-difluoro-3-((4-fluoro-2-methoxy-5-nitrophenoxy)methyl)-4-methoxybenzene);

[0017] Step (3): Dissolve compound B and reducing agent in reaction solvent. Under the action of catalyst, compound B and reducing agent undergo reduction reaction to obtain 5-[(2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-methoxyaniline (compound C);

[0018] Step (4): Under alkaline conditions and the action of triphosgene, 5-((2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-methoxyaniline and 4-aminothiophene-2,3-dicarboxylic acid dimethyl ester hydrochloride were synthesized by a one-pot condensation reaction to form thiophene urea derivative (compound D).

[0019] Step (5): Compound D reacts under alkaline conditions to generate Linzagolix.

[0020] In step (1), the molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to 2-methoxy-4-fluorophenol is 1:1 to 1:2, preferably 1:1 to 1:1.5, more preferably 1:1 to 1:1.25, and most preferably 1:1.05 to 1:1.15.

[0021] The alkali is selected from one of diethyl azobiscarbonate (DEAD), diisopropyl azobiscarboxylate (DIAD), and N,N-diisopropylethylamine (DIPEA), preferably DEAD or DIAD.

[0022] The molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to the base is 1:1 to 1:4, preferably 1:1 to 1:3, and more preferably 1:1 to 1:1.5.

[0023] The phosphine ligand is selected from one of triphenylphosphine (PPh3), tri(tert-butyl)phosphine (P(n-Bu)3), and (1,2-bis(ethoxycarbonyl)hydrazyl)triphenylphosphine trifluoromethanesulfonate (BEHT triflate), preferably triphenylphosphine.

[0024] The molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to phosphine ligand is 1:1 to 1:4, preferably 1:1 to 1:3, and more preferably 1:1 to 1:1.5.

[0025] The reaction solvent is selected from one or more low-polarity solvents such as tetrahydrofuran, diethyl ether, and dichloromethane, with tetrahydrofuran being preferred.

[0026] The temperature of the photoelongation reaction is 20–60°C, preferably 25–40°C; the time of the photoelongation reaction is 2–18 hours.

[0027] Specifically, when the organophosphorus ligand is selected from one or more of triphenylphosphine and tris(tert-butyl)phosphine, the Mitsunobu reaction time is 2 to 3 hours; when the organophosphorus ligand is selected from (1,2-bis(ethoxycarbonyl)hydrazino)triphenylphosphine trifluoromethanesulfonate, the Mitsunobu reaction time is 10 to 15 hours.

[0028] After the photoelectrophoresis reaction is complete, calcium bromide is added to the reaction solution, the mixture is stirred at room temperature, filtered, and the filtrate is diluted with water, extracted with ethyl acetate, and the organic phases are combined. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene; or after the photoelectrophoresis reaction is complete, saturated sodium bicarbonate aqueous solution is added, the mixture is extracted with dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by normal-phase silica gel column chromatography to obtain 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene; or after the photoelectrophoresis reaction is complete, the mixture is filtered, the filtrate is diluted with water, extracted with ethyl acetate, the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by normal-phase silica gel column chromatography to obtain 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene.

[0029] The molar ratio of calcium bromide to 2,3-difluoro-6-methoxybenzyl alcohol is 1:1 to 10:1, preferably 2:1 to 6:1. The phosphine oxy byproduct generated during the reaction is removed with calcium bromide to avoid column chromatography.

[0030] The eluent for the normal-phase silica gel column chromatography is petroleum ether: ethyl acetate = 5:1 V / V.

[0031] In step (2), the acidic solvent is one of glacial acetic acid, acetic anhydride and concentrated sulfuric acid, preferably glacial acetic acid.

[0032] The concentrated sulfuric acid has a mass fraction of ≥70%, specifically, the concentrated sulfuric acid has a mass fraction of 98%.

[0033] The molar ratio of compound A to nitric acid is 1:1.5 to 1:5.0, preferably 1:1.5 to 1:3.0.

[0034] Specifically, the molar ratio of compound A to nitric acid can be 1:2.

[0035] The nitric acid has a mass fraction of 68%.

[0036] The nitration reaction is carried out at a temperature of 40–80°C for 0.5–2 hours.

[0037] After the nitration reaction was completed, the reaction solution was cooled to room temperature, ice water was added, a solid precipitated, filtered, and dried to obtain compound B.

[0038] The volume ratio of ice water to acidic solvent is 2:1.

[0039] In step (3), the catalyst is selected from one or more of tetramethylethylenediamine, 4,4'-bipyridine, 2,2'-bipyridine, 2,2'-biimidazole, 4-dimethylaminopyridine, pyrazine, 1,2,4-triazole, and 8-hydroxyquinoline, preferably 4,4'-bipyridine or 2,2'-bipyridine.

[0040] The molar ratio of the catalyst to compound B is 0.1:1 to 2:1, preferably 0.2:1 to 1:1.

[0041] The reducing agent is selected from one or more of pinacol diborate (CAS No.: 73183-34-3), bis(catechol borate) (CAS No.: 13826-27-2), bis(neopentylethylene glycol) diborane (B2nep2, CAS No.: 201733-56-4), and tetrahydroxydiborane (CAS No.: 13675-18-8), preferably tetrahydroxydiborane.

[0042] The molar ratio of the reducing agent to compound B is 1:1 to 10:1, preferably 2:1 to 8:1, and more preferably 2:1 to 5:1.

[0043] The reaction solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, toluene, acetonitrile, acetone, ethyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide, and water, preferably N,N-dimethylformamide or dimethyl sulfoxide.

[0044] The temperature of the reduction reaction is 0–80°C, preferably 20–60°C, and more preferably 25–40°C; the time of the reduction reaction is 2 minutes to 1 hour, preferably 2 minutes to 0.5 hours.

[0045] Specifically, compound B is dissolved in a reaction solvent, a reducing agent is added, and a catalyst reaction solvent solution is added dropwise to carry out a reduction reaction. After the reaction is complete, the reaction solution is diluted with water, extracted with ethyl acetate, and the organic phases are combined. The organic phase is dehydrated by anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by normal-phase silica gel column chromatography to obtain compound C.

[0046] In step (4), the molar ratio of compound C to dimethyl 4-aminothiophene-2,3-dicarboxylate hydrochloride is 1:1.0 to 1:1.5, preferably 1:1.0 to 1:1.2.

[0047] The molar ratio of compound C to triphosgene is 1:1.0 to 1:1.5, preferably 1:1.0 to 1:1.2.

[0048] The alkaline conditions are provided by a base selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, and N,N-dimethylpyridine, preferably triethylamine.

[0049] The molar ratio of compound C to the base is 1:3.0 to 1:10.0, preferably 1:5.0 to 1:8.0.

[0050] The temperature of the condensation reaction is 0–40°C, preferably 20–40°C; the time of the condensation reaction is 0.5–10 hours, preferably 0.5–6 hours.

[0051] The reaction solvent is selected from dichloromethane and tetrahydrofuran, preferably dichloromethane.

[0052] In step (5), the alkali providing alkaline conditions is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide or its hydrate, sodium methoxide and sodium ethoxide, preferably lithium hydroxide or its hydrate.

[0053] The lithium hydroxide hydrate mentioned is lithium hydroxide monohydrate.

[0054] The molar ratio of compound D to the base is 1:2.0 to 1:10.0, preferably 1:4.0.

[0055] The reaction solvent is selected from at least one of methanol, ethanol, tetrahydrofuran, and water, preferably a mixed solvent of tetrahydrofuran, methanol, and water in a volume ratio of (1-6):1:1.

[0056] The reaction temperature is 25℃~40℃, and the reaction time is 1~4 hours.

[0057] After the reaction was completed, the reaction solution was diluted with water, the pH of the reaction solution was adjusted to acidic with dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to obtain Linzagolix.

[0058] Specifically, compound D was dissolved in the reaction solvent, a base was added, and the reaction was carried out. After the reaction was completed, the pH of the reaction solution was adjusted to acidic with hydrochloric acid, and water and ethyl acetate were added for extraction. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to obtain Linzagolix.

[0059] More specifically, when the reaction solvent is selected from a mixed solvent of tetrahydrofuran, methanol and water in a volume ratio of (1-6):1:1, compound D is dissolved in tetrahydrofuran, a mixed solvent of methanol and water is added, the mixture is stirred to dissolve, a base is added, and the reaction is carried out. After the reaction is completed, the pH of the reaction solution is adjusted to acidic with hydrochloric acid, and water and ethyl acetate are added for extraction. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain Linzagolix.

[0060] The advantages of this invention compared to existing technologies are as follows:

[0061] In this invention, 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene is prepared in one step by reacting 2,3-difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol via photo-extending reaction. This avoids the synthesis of the intermediate 2,3-difluoro-6-methoxybenzyl chloride, shortens the reaction steps, and increases the reaction yield from 30% in the original patent to over 65%, thereby improving the atom economy of the chemical reaction and the efficiency of the entire synthetic route.

[0062] The original patent uses metal reducing agents such as iron powder and nickel to reduce nitro compounds. The reaction temperature is high and the reaction time is long. Due to the presence of a large amount of metal, the reaction is often incomplete and the post-processing is difficult. The present invention changes the reaction reagent and can reduce nitro to amino in 5 minutes at room temperature with a yield of up to 90%, which is better than the original process.

[0063] The entire route is three steps shorter than the original process, improving the atom economy and synthesis efficiency of the chemical reaction;

[0064] The present invention features mild reaction conditions and simple post-processing operations, making it more convenient and efficient.

[0065] The Linzagolix prepared in this invention has high purity, the product quality obtained from repeated experiments is stable, and the post-processing is convenient, making it suitable for industrial production. Detailed Implementation

[0066] The specific embodiments of the present invention are described in detail below. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0067] Example 1

[0068] 2,3-Difluoro-6-methoxybenzyl alcohol (20 g, 114.9 mmol) was dissolved in 180 mL of tetrahydrofuran, and 2-methoxy-4-fluorophenol (17.1 g, 120.4 mmol) and triphenylphosphine (45.2 g, 172.4 mmol) were added. The reaction was carried out at 0 °C for 0.5 h. The temperature was lowered to -10 °C, and diisopropyl azodicarboxylate (34.8 g, 172.4 mmol) was added dropwise. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the mixture was filtered, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow oil. The oil was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 V / V) to give compound A in 80.1% yield.

[0069] 1 H NMR (400MHz, Chloroform-d) δ7.14 (q, J=9.6Hz, 1H), 6.96 (dd, J=8.8, 4.8Hz, 1H), 6.85-6.56 (m, 3H), 5.16 (d, J=2.0Hz, 2H), 3.86 (s, 6H).

[0070] Compound A (17 g, 57 mmol), acetic acid (100 mL), and nitric acid (68% nitric acid, 7.19 g, 114 mmol solute) were added to a reaction flask. The mixture was heated to 60 °C and reacted for 30 minutes. After the reaction was complete, the mixture was cooled to room temperature, and 200 mL of ice water was added. A yellow solid precipitated, which was filtered and dried to give compound B, with a yield of 91.2%.

[0071] 1 H NMR (400MHz, Chloroform-d) δ7.91(d,J=7.2Hz,1H),7.18(q,J=9.6Hz,1H),6.74(d,J=12.4Hz,1H),6.68-6.64(m,1H),5.28(s,2H),3.94(d,J=12.4Hz,6H).

[0072] Compound B (12 g, 34.98 mmol) was dissolved in N,N-dimethylformamide (60 mL), tetrahydroxydiborane (9.4 g, 104.9 mmol) was added, and a DMF solution (15 mL) of 4,4'-bipyridine (2.73 g, 17.49 mmol) was added dropwise. The reaction was carried out at room temperature for 5 min. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was concentrated, and normal-phase silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 V / V) was performed to separate and purify compound C, with a yield of 92.1%.

[0073] 1 H NMR(400MHz,Chloroform-d)δ7.14(q,J=9.2Hz,1H),6.68(d,J=11.6Hz,1H),6.64-6 .61(m,1H),6.58(d,J=8.8Hz,1H),5.12(d,J=2.0Hz,2H),3.86(s,3H),3.79(s,3H).

[0074] Compound C (12 g, 38.3 mmol) and triphosgene (12.5 g, 42.1 mmol) were dissolved in dichloromethane (50 mL), cooled to 0 °C, and triethylamine (31.9 mL, 229.8 mmol) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 30 min. Then, 4-aminothiophene-2,3-dicarboxylic acid dimethyl ester hydrochloride (11.5 g, 45.9 mmol) was added, and the mixture was reacted at room temperature for 2 h. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give compound D in 93.2% yield.

[0075] 1 H NMR(400MHz,Chloroform-d)δ8.84(s,1H),7.98(d,J=1.2Hz,1H),7.62(d,J=8.0Hz,1H),7.13(q,J=9.6Hz,1H), 6.74(d,J=11.6Hz,1H),6.60(d,J=9.2Hz,1H),6.52(s,1H),5.21(s,2H),3.94(s,3H),3.89(s,3H),3.85(s,6H).

[0076] Compound D (5 g, 9.0 mmol) was dissolved in tetrahydrofuran (60 mL), and a methanol-water mixture (20 mL, methanol:water = 1:1 V / V) was added. After stirring to dissolve, lithium hydroxide (866 mg, 36 mmol, 4.0 eq) was added, and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with water (10 mL), and the pH of the reaction solution was adjusted to 3 with 1 mol / L dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain Linzagolix with a yield of 51.6% and an HPLC purity of 98.95%.

[0077] 1H NMR (400MHz, DMSO-d6) δ14.56(s,1H),12.03(s,1H),7.50(q,J=9.6Hz,1H),7.41(s,1H),7.28( d,J=7.2Hz,1H),7.15(d,J=11.6Hz,1H),6.93(dt,J=9.2,2.4Hz,1H),4.97(s,2H),3.82(s,6H).

[0078] MS m / z (ESI): 507.0 [MH] + .

[0079] Example 2

[0080] 2,3-Difluoro-6-methoxybenzyl alcohol (10 g, 57.4 mmol) and 2-methoxy-4-fluorophenol (8.56 g, 60.26 mmol) were dissolved in tetrahydrofuran, and triphenylphosphine (22.6 g, 86.3 mmol) and DIAD (11.36 mL, 86.8 mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, calcium bromide (20 g, 115.5 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for another 6 hours. The mixture was filtered to obtain a filtrate, which was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow oil. The oil was cooled at -20 °C for 1 hour to obtain compound A (solid, yield 93.2%).

[0081] Example 3

[0082] Compared with Example 2, this example only replaces DIAD with an equal amount of DEAD, and all other aspects are the same as in Example 2. The yield of compound A is 91.8%.

[0083] Example 4

[0084] Compared with Example 2, this example replaced DIAD with an equal amount of DEAD and adjusted the amount of 2-methoxy-4-fluorophenol so that the molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to 2-methoxy-4-fluorophenol was 1:1.5. All other aspects were the same as in Example 2, and the yield of compound A was 83.6%.

[0085] Example 5

[0086] Compared with Example 2, this example replaced DIAD with an equal amount of DEAD and adjusted the amount of 2-methoxy-4-fluorophenol so that the molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to 2-methoxy-4-fluorophenol was 1:1.2. All other aspects were the same as in Example 2, and the yield of compound A was 87.8%.

[0087] Example 6

[0088] Compared with Example 2, this example uses an equal amount of tri-tert-butylphosphine to replace triphenylphosphine, and all other aspects are the same as in Example 2. The yield of compound A is 79.4%.

[0089] Example 7

[0090] 2,3-Difluoro-6-methoxybenzyl alcohol (5 g, 28.7 mmol, 1.0 eq) and 2-methoxy-4-fluorophenol (4.08 g, 28.7 mmol, 1.0 eq) were dissolved in 1,2-dichloroethane. (1,2-bis(ethoxycarbonyl)hydrazino)triphenylphosphine trifluoromethanesulfonate (BEHT Triflate, 20.2 g, 34.45 mmol, 1.2 eq) and N,N-diisopropylethylamine (DIPEA, 4.95 mL, 28.7 mmol, 1.0 eq) were added. The reaction was carried out at room temperature for 15 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to normal-phase silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 V / V). The purified product was an oily substance, cooled, and compound A (solid, yield 64.2%) was obtained.

[0091] Example 8

[0092] Compared with Example 7, the amount of DIPEA was adjusted in this example, while the rest were the same as in Example 7, and the yield of compound A was 71.4%.

[0093] Table 1. Effect of reaction process on the yield of compound A

[0094]

[0095]

[0096] Note: a is the molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to 2-methoxy-4-fluorophenol; b is the molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to the base; c is the molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to the phosphine ligand.

[0097] Example 9

[0098] Compound B (12 g, 34.98 mmol) was dissolved in N,N-dimethylformamide (60 mL), and tetrahydroxydiborane (9.4 g, 104.9 mmol) was added. Then, a DMF solution (15 mL) of 4,4'-bipyridine (2.73 g, 17.49 mmol) was added dropwise. After the addition was complete, the reaction was carried out at room temperature (25 °C) for 10 min. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to normal phase silica gel column chromatography (eluting agent: oil ether / ethyl acetate = 10 / 1 V / V) to purify compound C (solid, yield 92.4%).

[0099] Example 10

[0100] Compared to Example 9, this example only replaces the catalyst 4,4'-bipyridine in Example 9 with an equal amount of 2,2'-bipyridine. The rest is the same as in Example 9, and the yield of compound C is 81.2%.

[0101] Example 11

[0102] Compared with Example 9, the only difference in this example is that the solvent DMF in Example 9 was replaced with an equal volume of DMSO. The rest is the same as in Example 9, and the yield of compound C is 87.2%.

[0103] Example 12

[0104] Compared with Example 9, the only difference in this example is that the reducing agent tetrahydroxydiborane in Example 9 was replaced with an equal amount of pinacol diborate. The rest is the same as in Example 9, and the yield of compound C is 71.6%.

[0105] Example 13

[0106] Compared with Example 9, the only difference in this example is that the reducing agent tetrahydroxydiborane in Example 9 was replaced with an equal amount of di-catechol borate ester. The rest is the same as in Example 9, and the yield of compound C is 88.4%.

[0107] Table 2. Effect of reaction process on the yield of compound C

[0108]

Claims

1. A method for preparing Linzagolix, characterized in that: The synthesis route is as follows: The process includes: using 2,3-difluoro-6-methoxybenzyl alcohol as a raw material, under the action of a base and a phosphine ligand, 2,3-difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol undergo a photo-echoic reaction to obtain 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene; 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene undergoes a nitration reaction and a reduction reaction to obtain 5-[(2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-methoxyaniline; under alkaline conditions and the action of triphosgene, 5-[(2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-methoxyaniline reacts with 4-aminothiophene-2,3-dicarboxylic acid dimethyl ester hydrochloride in a one-pot condensation reaction to obtain a thiophene urea derivative; the thiophene urea derivative is then converted into Linzagolix under alkaline conditions.

2. The method for preparing Linzagolix according to claim 1, characterized in that: Includes the following steps: Step (1): 2,3-Difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol are dissolved in a reaction solvent. Under the action of a base and a phosphine ligand, 2,3-difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol undergo a photo-tracing reaction to obtain 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene; Step (2): In an acidic solvent, 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene undergoes a nitration reaction with nitric acid to obtain 1,2-difluoro-3-((4-fluoro-2-methoxy-5-nitrophenoxy)methyl)-4-methoxybenzene; Step (3): 1,2-Difluoro-3-((4-fluoro-2-methoxy-5-nitrophenoxy)methyl)-4-methoxybenzene and a reducing agent are dissolved in a reaction solvent. Under the action of a catalyst, 1,2-difluoro-3-((4-fluoro-2-methoxy-5-nitrophenoxy)methyl)-4-methoxybenzene undergoes a reduction reaction with the reducing agent to obtain 5-[(2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-methoxyaniline; Step (4): Under alkaline conditions and the action of triphosgene, 5-((2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-methoxyaniline and 4-aminothiophene-2,3-dicarboxylic acid dimethyl ester hydrochloride were synthesized by a one-pot condensation reaction to form thiophene urea derivatives. Step (5): Thiophene urea derivatives react under alkaline conditions to generate Linzagolix.

3. The method for preparing Linzagolix according to claim 1 or 2, characterized in that: The molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to 2-methoxy-4-fluorophenol is 1:1 to 1:2, preferably 1:1 to 1:1.5, more preferably 1:1 to 1:1.25, and most preferably 1:1.05 to 1:1.

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4. The method for preparing Linzagolix according to claim 1 or 2, characterized in that: The base is selected from one of diethyl azobiscarbonate or diisopropyl azobiscarboxylate, N,N-diisopropylethylamine, preferably diethyl azobiscarbonate or diisopropyl azobiscarboxylate; the molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to the base is 1:1 to 1:4, preferably 1:1 to 1:3, more preferably 1:1 to 1:1.5; the phosphine ligand is selected from one of triphenylphosphine, tris(tert-butyl)phosphine, (1,2-bis(ethoxycarbonyl)hydrazyl)triphenylphosphine trifluoromethanesulfonate, preferably triphenylphosphine; the molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to the phosphine ligand is 1:1 to 1:4, preferably 1:1 to 1:3, more preferably 1:1 to 1:1.

5.

5. The method for preparing Linzagolix according to claim 1 or 2, characterized in that: The reaction solvent is selected from one or more low-polarity solvents such as tetrahydrofuran, diethyl ether, and dichloromethane, with tetrahydrofuran being preferred.

6. The method for preparing Linzagolix according to claim 1 or 2, characterized in that: The temperature of the photoelongation reaction is 20–60°C, preferably 25–40°C; the time of the photoelongation reaction is 2–18 hours.

7. The method for preparing Linzagolix according to claim 2, characterized in that: The acidic solvent is one of glacial acetic acid, acetic anhydride, and concentrated sulfuric acid, preferably glacial acetic acid; the molar ratio of 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene to nitric acid is 1:1.5 to 1:5.0, preferably 1:1.5 to 1:3.0; the nitration reaction temperature is 40 to 80°C, and the nitration reaction time is 0.5 to 2 hours.

8. The method for preparing Linzagolix according to claim 2, characterized in that: The catalyst is selected from one or more of tetramethylethylenediamine, 4,4'-bipyridine, 2,2'-bipyridine, 2,2'-biimidazole, 4-dimethylaminopyridine, pyrazine, 1,2,4-triazole, and 8-hydroxyquinoline, preferably 4,4'-bipyridine or 2,2'-bipyridine; the molar ratio of the catalyst to 1,2-difluoro-3-((4-fluoro-2-methoxy-5-nitrophenoxy)methyl)-4-methoxybenzene is 0.1:1 to 2:1, preferably 0.2:1 to 1:1; the reducing agent is selected from one or more of pinacol diboronate, bis(catechol borate), bis(neopentylethylene glycol)diborane, and tetrahydroxydiborane, preferably tetrahydroxydiborane; The molar ratio of the reducing agent to 1,2-difluoro-3-((4-fluoro-2-methoxy-5-nitrophenoxy)methyl)-4-methoxybenzene is 1:1 to 10:1, preferably 2:1 to 8:1, and more preferably 2:1 to 5:1; the reaction solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, toluene, acetonitrile, acetone, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and water, preferably N,N-dimethylformamide or dimethyl sulfoxide; the temperature of the reduction reaction is 0 to 80°C, preferably 20 to 60°C, and more preferably 25 to 40°C; the time of the reduction reaction is 2 minutes to 1 hour, preferably 2 minutes to 0.5 hours.

9. The method for preparing Linzagolix according to claim 1 or 2, characterized in that: The molar ratio of 5-[(2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-methoxyaniline to dimethyl 4-aminothiophene-2,3-dicarboxylate hydrochloride is 1:1.0 to 1:1.5, preferably 1:1.0 to 1:1.2; the molar ratio of 5-[(2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-methoxyaniline to triphosgene is 1:1.0 to 1:1.5, preferably 1:1.0 to 1:1.

2. The reaction ratio is 1:1.0 to 1:1.2; the alkaline condition is provided by a base, which is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, and N,N-dimethylpyridine, preferably triethylamine; the reaction solvent is selected from one of dichloromethane and tetrahydrofuran, preferably dichloromethane; the temperature of the condensation reaction is 0 to 40°C, preferably 20 to 40°C; the time of the condensation reaction is 0.5 to 10 hours, preferably 0.5 to 6 hours.

10. The method for preparing Linzagolix according to claim 1 or 2, characterized in that: The alkali providing alkaline conditions is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide or its hydrate, sodium methoxide and sodium ethoxide, preferably lithium hydroxide or its hydrate; the reaction solvent is selected from at least one of methanol, ethanol, tetrahydrofuran and water, preferably a mixed solvent of tetrahydrofuran, methanol and water in a volume ratio of (1-6):1:1; the reaction temperature is 25℃-40℃ and the reaction time is 1-4 hours.

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